Lymphovenous Canada: Liver toxicity raises doubts about coumarin

Seemingly unpredictable instances of liver toxicity through the use of coumarin, an anti-lymphedema drug and lack of scientific evidence that the drug works, has led to the suspension of drug sales in Australia, France, Belgium and Canada.

Coumarin (1,2-benzopyrone or 5,6-benzo-[alpha]-pyrone) (not related to the anticoagulant coumadin), is or has been marketed as Lodema in Australia, Lysedem in France and Venalot Depot tablets in Belgium. Coumarin is most commonly sold as tablets and capsules but is also marketed as an injection or ointment/liniment.

Coumarin has been used since the mid-1980's to reduce lymphedema, and more recently, on an experimental basis by itself and in combination with other drugs, to treat patients with some advanced forms of cancer (such as renal cell carcinoma and malignant melanoma) (Marshall ME et al., Journal of Biological Response Modifiers 8:62-69 1989.)

Coumarin was originally obtained from the tonka bean and lavender oil but is now synthetically produced. The U.S. National Cancer Institute [U.S.A.} notes: "Coumarin was formerly used in the United States as a fixative and flavoring agent in foods and as a pharmaceutical excipient. In response to investigations conducted by coumarin manufacturers which demonstrated that coumarin produced liver toxicity in animals that were given the substance in amounts comparable to or greater than what appeared in human foods, coumarin was in 1954 recategorized by the United States Food and Drug Administration (FDA) as a food adulterant. Since that time, its addition to human foods has been prohibited and importing coumarin-containing foodstuffs from outside the U.S. is not permitted."

As a result of its potentially toxic affect on the liver (hepatotoxicity) - in some cases leading to death - the use of oral coumarin in a number of countries has been restricted or suspended.

In Australia the drug Lodema was suspended in August 1996 when the Australian Drug Evaluation Committee received 10 reports of patients who developed abnormalities in liver function tests or more serious signs of hepatotoxicity (including two deaths) associated with the use of tablets containing 200 mg of courmarin. (WHO Drug Information Vol. 10, No. 4, 1996). In France, it was first approved in 1986 for use in lymphedema following radiation for breast cancer. Over an eight year period, 34 cases of hepatotoxicity were reported, of which all but three were able to reverse the toxcity by stopping the use of the drug.

It was these three cases which lead the medicines agency in France to suspend the drug. Following France's action, the drug was suspended in Belgium by its Belgium distributor. (Coumarin suspended in France, Scrip, 1997; 25 Feb: 20).

Lodema is not available for sale in Canada. The Special Access Program of the Health Protection Branch, Health Canada does not allow patients to receive Coumarin as an emergency drug.

Ointments and liniments applied to the skin appear to be less toxic, some studies suggesting that they have virtually no therapeutic affect. [Becley-Kartey SA, Hotchkiss SA, Capel M. (of Imperial College School of Medicine at St. Mary's, London, U.K.) Comparative in vitro skin absorption and metabolism of coumarin. Toxicology and Applied Pharmacology 145, 34-42(1997).]

In a report of the June 1995 meeting of the Australian Drug Evaluation Committee (ADEC), leading to the suspension of the drug in that country, the ADEC noted, "there are insufficient data to support the efficacy of topical coumarin preparations (powder or ointment) in the treatment of lymphoedema due to any cause."

Humans appear to metabolize coumarin differently than other species. With rats, toxicity of the liver is dose-related, whereas coumarin-induced hepatoxity in humans appears not to be dose related. (Brief Case Reports, AJG, Vol. 92, No. 2, 1997 Prodyot Ghosh, Rodney Markin and Michael Sorrell, University of Nebraska Medical Centre, Omaha, Nebraska)

Although liver toxicity in humans is rare, most troubling is that there appears to be no predictability between liver damage and other factors such as age, prior surgery and/or radiotheapy, prior history of cellulitis, duration of lymphedema, time since previous surgery, or the concomitant use of tamoxifen (Coumarin-induced hepatoxicity, Correspondence, Loprinzi Cl, Sloan J Kugler J., Mayo Clinic, Journal of Clinical Oncology 1997: 15(9):3167-8).

Some researchers have noted that the effect of this drug on the liver is "idiosyncratic". (Brief Case Reports, AJG, Vo. 92, No. 2, 1997 Prodyot Ghosh, Rodney Markin and Michael Sorrell, University of Nebraska Medical Centre, Omaha, Nebraska). The long-term affects of this drug on the liver have not been determined.

The rates of liver toxicity estimated to the numbers of people taking coumarin vary widely among researchers.

• Casley-Smith et al of the Lymphoedema Association of Australia have sponsored the production of Lodema through their association. The Association has supported seven trials, five of which have been reported, which involved 1106 patients over a 14.6 month period. Casley-Smith suggests an average rate of only 0.22% persons developing symptoms of liver toxicity when taking oral doses of coumarin.

  They suggest that patients have their liver tested and the drug withdrawn if they develop signs of liver malfunction. John R. Casley-Smith and Judith Casley-Smith, Frequency of coumarin hepatotoxicity, Medical Journal of Australia, Vol. 162, 3 April 1995.

• Studies undertaken at the Mayo Clinic in the U.S., however, have been unable to duplicate the results of the Casley-Smiths and report a rate of liver toxicity in persons who have taken oral doses of the drug in their study of 6%. The Mayo Clinic study required all participants, however, to take liver tests regardless of whether they exhibited outward signs of liver toxicity. Coumarin-induced hepatoxicity, Correspondence, Loprinzi Cl, Sloan J Kugler J., Mayo Clinic, Journal of Clinical Oncology 1997: 15(9):3167-8.

Patients who are taking or who have taken coumarin in the past are strongly encouraged to have their liver function tested.

References:

1. Marshall ME et al. Effects of coumarin (1,2 Benzopyrone) and cimetidine on peripheral blood lymphocytes, natural killer cells and monocytes in patients with advanced malignancies. J Biol Response Mod 1989; 8(1): 62-9
2. Koch S, Beurton I et al. Coumarin-induced acute cytolytic hepatitis. Two cases. Gastroenterologie Clinique et Biologique 1997; 21: 223-5 (In French)
3. Coumarin Suspended in France. Scrip, 1997; 25 Feb: 20
4. Gosh P, Markin RS et al Coumarin induced hepatic necrosis. American Journal of Gastroenterology 1997; 92: 348-9
5. Morrison L, Welsby PD. Side effects of coumarin. Postgraduate Medical Journal 1995, 71, 701-2
6. Lodema and the liver. Reactions, 1995; 565: 3
7. Bassett ML, Dahlstrom JE. Liver failure while taking coumarin. Medical Journal of Australia 1995; 163:106
8. Beinssen APA. Possible coumarin hepatotoxicity. Medical Journal of Australia. 1994; 161: 725
9. Coumarin: regulatory action. WHO Drug Information 1996; 10(4): 188-9
10. Coumarin: a strong association with hepatotoxicity. WHO Drug Information 1995; 9(3): 159
11. Casley-Smith JR. Frequency of coumarin hepatotoxicity. Medical Journal of Australia 1995.; 162(7): 391
12. Loprinzi CL, Sloan J Kugler J. Lack of Effect of Coumarin in Women with Lymphedema after Treatment for Breast Cancer. The New England Journal of Medicine. 1999; 340;346-50.
    Coumarin induced hepatotoxicity. Journal of Clinical Oncology 1997; 15(9): 3167-8
13. Becley-Kartey SA, Hotchkiss SA, Capel M. Comparative in vitro skin absorption and metabolism of coumarin. Toxicology and Applied Pharmacology 145, 34-42(1997).
14. National Cancer Institute, 1997, "Lymphedema" web page on CancerNet web site at http://cancernet.nci.nih.gov/clinpdq/supportive/Lymphedema_Physician.html
15. Cox D., O'Kennedy R., Thornes RD. The Rarity of Liver Toxicity in Patients Treated with Coumarin (1,2-benzopyrone). Human Toxicology 1989, Nov. 8(6):501-6.